{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:38:20Z","timestamp":1791581900583,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program","doi-asserted-by":"crossref","award":["2023YFC2506300"],"award-info":[{"award-number":["2023YFC2506300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Hainan Provincial Natural Science Foundation of China","award":["826QN0905"],"award-info":[{"award-number":["826QN0905"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Periodontitis is a chronic inflammatory disease remaining elusive with its pathogenesis. Mitochondrial dysfunction and aberrant immune activation are implicated, but the underlying mechanisms remain incompletely understood. Given the essential role of Ca2+ homeostasis in maintaining normal mitochondrial function, we investigated the role of mitochondrial calcium (mtCa2+) dysregulation in periodontitis. Gingival tissues from periodontitis patients and healthy controls, as well as cultured gingival fibroblasts stimulated with Porphyromonas gingivalis lipopolysaccharide, were examined using transmission electron microscopy, confocal imaging, flow cytometry, qPCR, and western blotting. Notably, mtCa2+ was overloaded under inflammatory conditions, accompanied by disruption of whole-cell Ca2+ homeostasis. We also observed marked mitochondrial ultrastructural damage, mitochondrial DNA (mtDNA) leakage, and activation of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway. The mitochondrial Ca2+ channel proteins, voltage dependent anion channel 1 (VDAC1) and mitochondrial calcium uniporter (MCU), were significantly upregulated in periodontitis gingiva, and their expression positively correlated with probing depth. Pharmacological inhibition of VDAC1 or MCU attenuated mtCa2+ overload, reduced mtDNA release and downregulated pro-inflammatory cytokines. These findings link mtCa2+ overload to mtDNA leakage and innate immune activation in periodontitis, and identify VDAC1 and MCU as promising therapeutic targets to restore mtCa2+ homeostasis and control host immune responses.<\/jats:p>","DOI":"10.3390\/ijms27104317","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitochondrial Calcium Overload Drives mtDNA-cGAS-STING Activation via VDAC1 and MCU Upregulation in Periodontitis"],"prefix":"10.3390","volume":"27","author":[{"given":"Xinyi","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-4625","authenticated-orcid":false,"given":"Yu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5336-8712","authenticated-orcid":false,"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"},{"name":"Peking University Hospital of Stomatology Sanya Division (Sanya Stomatology Center), Sanya 572014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxian","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/prd.12221","article-title":"Periodontitis: Facts, fallacies and the future","volume":"75","author":"Slots","year":"2017","journal-title":"Periodontology 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123713","DOI":"10.1016\/j.biomaterials.2025.123713","article-title":"Nanotherapeutics for microenvironment modulation and immune homeostasis in periodontitis treatment","volume":"326","author":"Zhou","year":"2026","journal-title":"Biomaterials"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1177\/00220345231151921","article-title":"The Role of Gingival Fibroblasts in the Pathogenesis of Periodontitis","volume":"102","author":"Wielento","year":"2023","journal-title":"J. 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